Dr. Lee's Alzheimer's and Antipsychotic lecture Flashcards
(68 cards)
1
Q
What is the term for a drop in cognitive function from a prior level?
A
mild cognitive impairment
2
Q
What is mild cognitive impairment plus a loss in the ability to care for oneself?
A
Dementia
3
Q
What is required to make the diagnosis of dementia?
A
A detailed history about prior levels of function.
4
Q
Is MCI treated with any medication? Dementia?
A
No and yes
5
Q
What rank in cause of death is Alzheimer’s?
A
6th in the USA
6
Q
What gene increases the risk of Alzheimer’s?
A
Apolipoprotein E (APOE). Varient E4 increases the risk. A single copy increases risk 3-fold, homozygous e4 increases risk 8-12 fold.
7
Q
What other family history increases the risk of Alzheimer’s?
A
Cardiovascular disease history in the family
8
Q
What lifestyles/disease states increase the risk of Alzheimer’s?
A
Cardiovascular disease in middle age Smoking Midlife obesity Midlife hypertension midlife hyperlipidemia diabetes
9
Q
What increases cognitive reserve to stave off dementia?
A
Education
10
Q
What maintains cognitive reserve?
A
social engagement
11
Q
What is the most common form of dementia (60-80%)?
A
Alzheimer’s
12
Q
In normal aging, neurons are…
A
preserved
13
Q
In normal aging, brain mass is…
A
preserved
14
Q
In normal aging, synaptic connections are…
A
lost. this is shown by processing speed decrease and abstract concept linkage decrease.
15
Q
How are storage of memories affected by normal aging?
A
Takes longer to develop memories
16
Q
How are retrieval of memories affected by normal aging?
A
Preserved, but retrieval process is slower.
17
Q
How is thinking and reasoning affected by normal aging?
A
Preserved
18
Q
What part of the brain is affected early in Alzheimers compared to normal aging?
A
The hippocampus (memory)
19
Q
What other area of the brain are different in Alzheimer’s compared to normal aging?
A
- Language is affected
- The ventricles start to enlarge
- As more cells die, the sulci get wider
20
Q
What areas of the brain are rich in cholinergic neurons?
A
Early: Memory Language Later: Reasoning and understanding Disinhibition and behavioral problems
21
Q
What histology will you see in Alzheimer’s Disease?
A
Amyloid beta peptide insoluble plagues accumulated on the outside of cells.
22
Q
What protein is formed with B-secretase and y-secretase?
A
Amyloid-beta42.
23
Q
What protein is formed from alpha-secretase and y-secretase?
A
B-amyloid40.
24
Q
Is amyloid-beta42 or beta-amyloid40 more plaque-forming?
A
Amyloid-beta 42 is more plaque-forming, while 40 is more soluble.
25
What is the original protein that is cut to form both amyloid-beta 42 and beta-amyloid 40?
APP - amyloid precursor protein
26
What stabilizes microtubules inside a neuron?
Hyperphosphorylated tau protein.
27
What is the cholinergic hypothesis for Alzheimer's?
That the loss of cholinergic neurons is responsible for AD. This is now considered a downstream event (aka something is killing these neurons, causing AD).
28
What is the amyloid-beta hypothesis? What is wrong with this hypothesis?
A-beta is the initial pathology leading to inflammation and neuronal death. However, almost all adults have A-beta, and A-beta load does not correlate with AD symptoms.
29
What is Tau Hypothesis?
Tau-hyperphosphorylation and neurofibrillary tangles is the single common pathway that leads to PD. Tau hypothesis is gaining ground as the predominant hypothesis.
30
What is the inflammation hypothesis?
Inflammation is a common event in AD. Nonspecific inflammation damages neurons causing A-beta and NFT (Neurofibrillary tangles). Many believe this is a marker of neuronal damage rather than the cause.
31
What is the novel hypothesis?
Impaired glucose transport hypothesis: The brain uses 20% of the body's energy, but only 2% of the body's weight. Disruption of energy can lead to:
- oxidative stress
- free radical formation
- Inflammation
- Neuronal Death
- Insulin resistance (diabetes)
- Decreased brain blood flow (vascular disease)
32
What is the consensus about AD?
That the disease is multifactorial since there is no single hypothesis. There is no single cause and no single cure. This is common between cancer and AD.
33
What is the usual time between development of amyloid plaques and the development of AD symptoms?
10 years or so
34
What does a mini-mental state exam (MMSE) score of 26-30 mean?
This is the preclinical stage. No symptoms have occurred, only biomarker changes. (eg only A-beta or tau in the blood or in the cerebrospinal fluid. MRI of the brain).
Controversial since there is no agreed-upon biomarker.
35
What does a MMSE score of 22-26 mean?
mild cognitive impairment. cognitive changes have occurred, but no functional changes.
36
What does an MMSE score of less than 22 mean?
Dementia due to AD. Mild, moderate, and severe are all categories. Cognitive and functional impairments have occurred.
37
What are characteristics of mild AD?
- problems coming up with the right word
- trouble remembering names when introduced to new people
- greater difficulty performing tasks in social or work settings
- losing or misplacing a valuable object
- increasing trouble with planning or organizing
38
What are characteristics of moderate AD?
- forgetfulness of events or personal history
- moody or withdrawn in social or mentally challenging situations
- unable to recall address, phone number, or high school that was graduated from
- confusion about what day it is
- need help choosing clothes for season/occasion
- changes in sleep habits/patterns: increased sleeping during the day
- increased risk of wandering and becoming lost
- personality or behavior changes, including suspicions, repetitive behavior
39
What are some characteristics of severe AD (late stage)?
- full-time care required
- lose awareness of recent experiences/surroundings
- high level of assistance required for daily living
- physical abilities changes, such as walking, sitting, and swallowing (eventually)
- increased difficulty communicating
- vulnerability to infections, especially pneumonia
40
What is the difference as far as slope between AD and vascular dementia?
AD has a steady decline in cognitive function (2 pts of MMSE every year) vs vascular dementia has a stepwise decrease in slope in accordance with a new infarction or narrowing of an artery
41
What % of dementia is vascular dementia?
10-20%
42
When is memory affected in vascular dementia?
Memory is generally preserved until later, depending on where the infarcts are. Motor symptoms can occur.
43
Does dementia usually occur on its own, or in conjunction with other disease states?
Usually co-occurs with other dementias. Share same risk factors. Modifies slope to be in the middle between the two.
44
What disease state shares pathology with Lewy body dementia? What is this caused by?
PD. Abnormal folding of the alpha-synuclein protein.
45
What symptoms are present with Lewy-body dementia?
Inattention
Executive dysfunction
Visuospatial impairment
Visual hallucinations are more common
Memory loss less prominent (physical symptoms more seen)
Lewy bodies are seen in later PD often development into lewy-body dementia
Physical symptoms of PD and the dementia of Lewy body
46
What is another name for Frontotemporal dementia? Why is it called this? What %age of dementias are this one?
Pick's disease. There are no active areas in the frontotemporal region. 2%.
47
What is one of the most common early-onset dementias?
Pick's disease
48
What symptoms go along with Pick's disease?
- disinhibition, apathy, loss of empathy
- aphasia: word-finding difficulty, halted speech
- often confused with depression
- does well on cognitive testing, memory and executive function preserved
49
What areas of the brain are inactive for AD?
The hippocampus and temporal lobe. (Hippocampus for short-term memories, and temporal lobe for long-term memory, visual and auditory input, language recognition).
50
What are the two approved treatments for AD?
Cholinesterase inhibitors
| NMDA antagonist
51
What drugs are cholinesterase inhibitors?
```
Donepezil
Galatamine
Rivastigmine
Tacrine - still approved, no longer marketed due to hepatotoxicity
(mild to severe)
```
52
What drug is an NMDA antagonist?
Memantine (moderate to severe)
53
How do cholinesterase inhibitors act?
They increase the ACh at the synaptic cleft by stopping breakdown of ACh at postsynaptic neurons.
54
Cholinesterase inhibitors;
- Function?
- If removed?
- How do you choose?
- Efficacy is limited, does not increase function. Delays symptoms for 6 months. Not disease modifying.
- If removed, pt would return to their lower level of functioning as if they were never on the Cholinesterase inhibitor
- choice is based upon tolerability
55
What are the adverse effects of cholinesterase inhibitors?
Gi: nausea, vomiting, diarrhea (up to 50% for rivastigmine)
Anorexia, weight loss, pain (up to 25%)
Bradycardia, dizziness, syncope (up to 25%)
muscle tremor, weakness (23%), urinary incontinence (3%)
Insomnia, vivid dreams (up to 15%)
56
How often should you increase cholinesterase inhibitors?
every 4-6 weeks. Goal is highest tolerable dose.
57
What is the mechanism of an NMDA antagonist?
Binds once channel is open, prevents overstimulation by glutamate. Blocks the channel. Could be disease modifying, but no evidence.
58
How do you use memantine?
In mono therapy (if cholinesterase is not tolerated) or in combo with cholinesterase inhibitor if dementia is severe.
59
What is the efficacy of one type of therapy for AD over another?
If mono therapy, very similar efficacy. Dual therapy slightly better than either of the mono therapies.
60
What are the side effects of memantine in comparison to ChE inhibitors?
Very mild SEs.
61
What are currently first line?
ChE inhibitors, probably because generic was available. Yes are worse.
62
What is second-line?
Memantine, but now generic is available. SEs are better, med is better tolerated. Efficacy is similar.
63
What are four targets for research?
1) B-A Cascade, predominate target, with little progress
- phase I studies have shown to decrease B-A and inflammatory biomarkers. However, need to start earlier and hard to find candidates without doing a population-wide study. Posiphen keeps APP from forming :clears B-A from brain: AB42 is not formed
2) Tau: TRx0237 is a prodrug for methylthionium chloride
3) Insulin (SR-Exenatide, nasal insulin, Kaiser study)
4) Inflammation (statins, NSAIDS... not successful)
64
Which medications have dose-limiting side effects?
ChE inhibitors
65
What will future treatments most likely target?
Tau, inflammation, and insulin resistance. Maybe multiple targets at once on a population-wide scale necessary to prevent.
66
What is the incidence of delirium in hospitalized older adults?
30%
67
What is the incidence of delirium in older adults hospitalized for his fractures or injurious falls?
50%
68
What percent of delirium is missed in hospitalized older adults?
70%
